Injectable hormone preparations



United States Patent 2,987,440 INJECTABLE HORMONE PREPARATIONS Karl Junkmann, Berlin, Josef Kathol, Berlin-Charlottenburg, and Hans Richter, Berlin-Steglitz, Germany, as-

signors to Schering A.G., Berlin, Germany, a corpora- "tion of Germany N Drawing. Filed Mar. 17, 1958, Ser. No. 721,646

2 Claims. (Cl. 167-65) This invention relates to an injectable preparation comprising steroid hormones and/or non-steroid hormones having the activity of such steroid hormones and more particularly to an injectable preparation of a high concentration in such steroid hormones and/or non-steroid hormones, said preparation being adapted to produce, on injection, a hormone depot of prolonged activity, and to a niethod of making such preparation. This application is a continuation-in-part of our prior copending application Serial No. 325,044, filed December 9, 1952 now abanboned, which is in turn a continuation-in-part of our prior copending application Serial No. 287,628, filed May 13, 1952 now Patent No. 2,840,508.

The hitherto most widely used method of administration of such hormones is by intramuscular injection of oleaginous solutions thereof. However, such injections must in many instances be repeated frequently at definite time intervals depending upon the resorbability of said hormone by the organism. As these repeated injections can be extremely irksome to the patient, in many cases, a method of treatment is employed which consists in the implantation of hormone crystals of suitable size, thereby setting up a depot in the organism, from which the latter can derive its requirements over a long period of time. The method of crystal implantation has however, for various reasons, not always proved satisfactory in practice. A primary reason is that it is in fact a surgical operation, although only a minor one.

Therefore, attempts have been made to replace the method of setting up a depot by crystal implantation by the more easily effected injection technique. Since narrow limits are placed upon the production of highly concentrated oleaginous solutions owing to the insuificient solubility of the hormones in oils, one method, which has been used, consists in the injection of crystal suspensions. However, this method also encounters certain ditficulties, particularly with respect to the preparation of such suspensions, and it can therefore in no wise be considered as ideal.

Some advance was made by the discovery of the socalled protracted effect which is possessed by certain esters of such hormones as compared with the free hormones. Administration of such esters rendered it possible to reduce the number of injections required; but even this method was limited by the relatively small size of the depot which could be set up by a single injection. It was not possible to produce sulficiently highly concentrated oleaginous solutions of such esters due to their insuflicient solubility in solvents conventionally used for intramuscular injection.

The present invention is in part based on the observation that it is possible to reduce the melting point of said hormones by converting them into their low melting esters or into low melting eutectic mixtures of esters. By this means, the melting point could be reduced to such an extent that the molten hormone compounds can be injected directly without further addition of a diluent in the same manner as the known oleaginous solutions.

The idea of injecting hormone preparations in the molten form instead of in the form of solutions is novel and hormone esters with sufiiciently low melting points were not heretofore known. Those hormones and derivatives thereof with high melting points which were Patented June 6, 1961 hitherto known had, in the non-crystalline state at room temperature, in practically all cases, the consistency of viscid resins or lacquers, whereas the melts produced according to the present invention, on cooling, crystallize only slowly and have the consistency of fluid oils.

It was also in no Way to be expected that it is possible to produce physiologically eilective hormone derivatives with such low melting point. Their application, by means of a simple injection, constitutes an essential simplification, as compared with implantation, in the setting up of comparatively large hormone depots in the organism.

Further additions may be advantageously made in order to dilute the hormone preparation so as to efiect better dosage, since in setting up depots of less than about mg., usually too great a proportion of an undesirable hormone preparation remains behind in the injection syringe. As suitable inert diluents there are employed solvents which are known and hitherto used for dissolving such hormones, for example fatty oils and higher glycols. Further additions may be made for improving their compatibility and for producing more protracted effects or for increasing absorption. For these purposes wax a1cohols are used with advantage.

The invention is based on the further observation, that there exists a series of heretofore unknown esters which are distinguished by their surprisingly high solubility in the usual solvents used for injection. This could not be expected since both the previously known esters of the lower fatty acids and also those of the higher fatty acids which were heretofore known, have exceedingly low solubilities in the oils concerned, as is evident from the following table. In this table there are listed the solubility of known steroid hormone compounds at room temperature in mg. per 1 com. of two typical solvents:

Sesame Rape seed Oil, mg. Oil, mg.

Testosterone 2 2 Testosterone propionate 12 18 Testosterone benzoate less than 2 less than 2 Pregnenol-(3)-one-(20) less than 1 less than 1 Preg-nenol-(3,S)-one-(20) acetate 20 15 Pregnenol-(3B)-one-(20) benzoa less than 2 less than 2 Desoxycorticosterone 8 7 Desoxycorticosterone acetate 4 2 Desoxycorticosterone butyrate 15 4 Desoxycorticosterone palmitate... 10 3 Desoxycortlcosterone stearate less than 5 Estradiol 1 0. 5 Esu'adiol-3-monobenzoateless than 1 2 Estrarliol-S, 17-dipr0pionate 20 A search for other more suitable solvents did not produce satisfactory results, since only very few of such solvents are tolerated by the body.

The above given table shows clearly that hormone esters with low molecular acids as well as esters with high molecular acids are. only slightly soluble in vegetable oils.

In accordance with this invention, the surprising discovery has been made that the hormone esters of aliphatic acids which have six, seven, or eight carbon atoms exhibit an especially high degree of oil solubility'which makes it possible to prepare for the first time, highly concentrated, fluid, substantially water-free injectable hormone preparations, in which the hormone is present in concentrations of at least 50 mg. per cc., and even more, at body temperatures. These high concentrations are in striking contrast to the relatively low concentrations in vegetable oils possible with presently known esters, as shown in the above table, which demonstrates clearly that only relatively small amounts, not exceeding 20 mg. per cc. of solvent at most, of the known esters are soluble in the conventionally used vegetable oils. The present invention, for the first time, permits the administration to patients of large doses of steroid and like hormones by a single injection of a liquid concentrated hormone preparation.

In accordance with this invention, hormone esters having especially favorable oil solubility characteristics may be prepared from caproic, oenanthic, or caprylic acids, the preferred esters being those of testosterone and hexestrol. Examples of testosterone esters include the caproate, the oenanthate, and the caprylate, while examples of hexestrol esters include the dioenanthate and the dicaprylate. The preparation of the testosterone esters is described in Example 1 below. The preparation of the hexestrol esters is carried out analogously.

The novel esters may be incorporated molten if desired, in suitable oil carriers, including any of the injectable vegetable oils conventionally used for preparations of this type, such as, for example, sesame oil or rape seed oil, in accordance with known methods. In this highly concentrated form, these preparations have been successfully used for treatment of hormonal iIlSlJfiiClCHCY. For example, a substantially water-free solution of 250 mg. per cc. of testosterone oenanthate in an oil carrier, sold commerically under the designation Testoviron-Depot has been successfully used for treatment of testicular hormonal iusufiiciency, as described in articles by I. A. Schneider, Aerztliche Wochenschrift, vol. 7, pages 381- 385 (1952), and H. Hagedorn, Die Medizinische, 1952, No. 45.

The following examples illustrate the invention without, however, limiting the same thereto.

EXAMPLE 1 The heretofore unknown low melting testosterone esters set forth below are introduced into ampoules and are used as such without any further diluent or other addition for injection in the same manner oleaginous hormone solutions are used.

(a) Preparation of testosterone caproate A mixture of 10 g. of testosterone, 40 cc. of pyridine, and 20 cc. of caproic acid anhydride is heated to 125 C. for 1 /2 hours. The cooled reaction mixture is decome posed with water While stirring and cooling, allowing the (b) Preparation of testosterone oenanthate When using oenanthic acid anhydride in the place of caproic acid anhydride and proceeding in the same man- 'as described above under (a), testosterone oenanthate melting at 3637.5 C. is obtained.

() Preparation of testosterone caprylate In the same manner as described under (a), there is obtained, from testosterone and caprylic acid anhydride, testosterone caprylate melting at 44-45 C.

EXAMPLE 2 By melting together any two, or better all three, of the esters described in Example 1, in widely varying proportions, clear melts are obtained which at body temperature and even at considerably lower temperatures, remain more or less fluid and injectable.

To simplify production of injection preparations according to this example, one may produce said esters directly in mixture with each other by esterifying testosterone, instead of with the pure carboxylic acid anhydride concerned, directly with a mixture of all the desired carboxylic acid anhydrides.

EXAMPLE 3 Preparation of hexestrol xii-oenanthate and of hexestrol di-caprylate A mixture of 3 g. hexestrol [i.e. di-(4-hydroxy-phenyl)- p-hexane], 12 cc. of pyridine, and 6 cc. of oenanthic acid anhydride is heated for 2 hours to C. The reaction mixture is cooled, water is added thereto, and the mixture is stirred for 18 hours. It is then extracted with ether and the ether solution is subsequently'washed with N sulfuric acid, water, 5% sodium carbonate solution, and again with water. The ethereal extract is dried over anhydrous sodium sulfate and the ether is distilled 01f. The remaining oily crude ester crystallizes on spraying with some methanol and melts, on recrystallization from methanol at 79-8l C.

The preparation of the hexestrol di-caprylate, melting at 77-78 C., is carried out analogously.

These higher fatty acid esters of hexestrol have a better solubility in oily solvents than the lower esters and hexestrol itself. 3

For instance 50 mg. of hexestrol di-oenanthate or 50 mg., of hexestrol di-caprylate are soluble in 1 cc. of ethyl oleate at room temperature.

These solubilities can be further considerably increased by mixing the esters with each other.

We claim: a

1. An injectable, highly concentrated, substantially water-free repository hormone ester composition, fluid at body temperature, said composition consisting essentially of at least one hormone ester selected from the group consisting of testosterone caproate, testosterone oenanthate, testosterone caprylate, hexestrol dioenanthate, and hexestrol dicaprylate, and an injectable vegetable oil, said hormone ester being dissolved in said oil in an amount substantially exceeding 50 mg. per cc. of composition.

2. An injectable, highly concentrated, substantially water-free repository testosterone composition, fluid at body temperature, said composition consisting of testosterone oenanthate and an injectable vegetable oil, said testosterone oenanthate being dissolved in said oil in an amount substantially exceeding 50 mg. per cc. of composition. 7

References Cited in the file of this patent FOREIGN PATENTS Great Britain May 5, 1937 OTHER REFERENCES Chem. Abst., vol. 35, 1941, page 6587?. 

1. AN INJECTABLE, HIGHLY CONCENTRATED, SUBSTANTIALLY WATER-FREE REPOSITORY HORMONE ESTER COMPOSITION, FLUID AT BODY TEMPERATURE, SAID COMPOSITION CONSISTING ESSENTIALLY OF AT LEAST ONE HORMONE ESTER SELECTED FROM THE GROUP CONSISTING OF TESTOSTERONE CARPORATE, TESTOSTERONE OENANTHATE, TESTOSTERONE CAPRYLATE, HEXESTROL DIOENANTHATE, AND HEXESTROL DICAPRYLATE, AND AN INJECTABLE VEGETABLE OIL, SAID HORMONE ESTER BEING DISSOLVED IN SAID OIL IN AN AMOUNT SUBSTANTIALLY EXCEEDING 50 MG. PER CC. OF COMPOSITION. 